Soluble honokiol derivatives

ABSTRACT

The invention provides a soluble honokiol detivative (such as a water soluble honokiol derivative) and its application in antagonizing glycoprotein VI receptor and providing antioxidant and neuroprotective effects.

FIELD OF THE INVENTION

The present invention is related to the field of compounds, compositionsand methods for treatment or prevention. Particularly, the inventionprovides a soluble honokiol derivative (such as a water soluble honokiolderivative) and its application in antagonizing glycoprotein VI receptorand providing antioxidant and neuroprotective effects.

BACKGROUND OF THE INVENTION

Stroke is a medical condition in which the brain's blood vessels areclogged or broken, leading to brain cell ischemia or death or injury.World Health Organization data shows that stroke is the second mostfrequent cause of death and each year about 6.0 million deaths resultedfrom stroke. Stroke can be divided into two types, namely, hemorrhagicstroke and ischemic stroke (about 80% of all stroke cases) which causescerebral vascular thrombosis.

Honokiol obtained from the stem of Magnolia officinalis was reported tohave effects in improving brain damage caused by ischemic stroke and apotent antioxidant and neuroprotective effects. CN 103113264 discloses amagnolol derivative, a honokiol derivative and preparation method andapplication thereof. However, due to poor solubility in water or oil forhonokiol, it is not suitable for clinical use in the treatment ofischemic stroke.

SUMMARY OF THE INVENTION

The present disclosure provides a compound having Formula (I) asdisclosed herein. Certain embodiments include the compounds wherein R₁is phosphate; R₂ and R₃ are each independently C₂₋₆alkenyl; and R₄ andR₅ are each independently H; or a pharmaceutically acceptable saltthereof. Some embodiments, R₂ and R₃ are each independently ethenyl; ora pharmaceutically acceptable salt thereof. In one embodiment, thepharmaceutically acceptable salt is a sodium salt. Particularembodiments of the compound can be3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl bis(phosphate) or sodium3′,5-diallyl-[1,1′-biphenyl]-2,4′-diylbis(phosphate).

The present disclosure also provides a pharmaceutical composition, whichcomprises a therapeutically effective amount of a compound of Formula(I) and optionally one or more pharmaceutically acceptable carriersand/or excipients. In one embodiment, the pharmaceutical composition isin a dosage form.

The present disclosure also provides a method of antagonizingglycoprotein VI receptor, comprising administration of a therapeuticallyeffective amount of a compound of the present disclosure to a subject.In one embodiment, platelet aggregation can be inhibited by the method.

The present disclosure also provides a method of providing antioxidantand neuroprotective effects in a subject, comprising administering atherapeutically effective amount of a compound of the present disclosureto the subject. Certain embodiments of the method include that themethod reduces edema and does not cause hemorrhage. In the methodsdescribed herein, the compound has a prolonged half-life compared tohonokiol and/or converts to honokiol in plasma.

In one embodiment, the neuroprotective effect diminishes brain damage inthe subject. In a further embodiment, the brain damage is ischemicstroke.

In one embodiment, the administration is parenteral administration. In afurther embodiment, the parenteral administration is intravenous,intramuscular or intracranial administration.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1A shows coronal sections of 2,3,5-triphenyltetrazolium chloride(TTC)-stained brains after middle cerebral artery occlusion (MCAO) inthe vehicle group treated with an isovolumetric solvent (normal saline,intravenous [i.v.]), and groups treated with HP-TMU (0.25, 0.5 and 1mg/kg, i.v.) or honokiol (0.129, 0.258 and 0.516 mg/kg, i.v.; the dosesof honokiol were adjusted by the ratio of the molecular weight ofhonokiol to HP-TMU (266.33/514.22)) after 30 min-embolic occlusion. Thedensitometric analyses for the measurement of infarct volume and brainedema after treatment with HP-TMU or honokiol against embolic stroke inmice were shown in FIG. 1B & FIG. 1C, respectively. Data are presentedas the means±SEM (n=8). *P<0.05 compared with the vehicle group.

FIG. 2 shows bleeding time measured at 10 min after the i.v.administration of normal saline (isovolumetric control) or HP-TMU (0.5and 1 mg/kg, i.v.) for 30 min. Data are presented as the means±SEM(n=6). Each symbol represents the bleeding time of an individual mouse.

FIG. 3A and FIG. 3B show assays of neurobehavioral functions includingA. neurological severity scoring and B. the rotarod test, evaluationswere performed before and 24 and 48 h after surgery. All data arepresented as the means±SEM (n=8). * P<0.05, compared with the vehiclegroup.

FIG. 4A and FIG. 4B show the A. mean plasma concentrations of honokiolvs. time profile in five rats after intravenous injection of HP-TMU(●)or honokiol(

); and B. pharmacokinetic parameters of HP-TMU in rat plasma.

FIG. 5 shows that mice were subjected to middle cerebral arteryocclusion (MCAO) surgery for 30 min, and then treated with theisovolumetric vehicle control (normal saline, intravenous [i.v.]) orHP-TMU (1 mg/kg, i.v.) or edaravone (3 mg/kg, i.v.). The therapeuticeffects of HP-TMU on long-term recovery were evaluated by neurologicalseverity scoring before or 1, 2, 7, 14, and 28 days after surgery. Alldata are presented as the means±SEM (n=3). *P<0.05, compared with thevehicle control group.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present disclosure and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise. It is to be understood that both theforegoing general description and the following detailed description areexamples and explanatory only and are not restrictive of the subjectmatter claimed. In this application, the use of the singular includesthe plural unless specifically stated otherwise. In this application,the use of “or” means “and/or” unless stated otherwise. Furthermore, useof the term “including” as well as other forms, such as “includes,” and“included” is not limiting.

As used herein, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise.

As used herein, the term “prodrug” refers to a compound (e.g., a drugprecursor) that is transformed in vivo to yield a parent compound or apharmaceutically acceptable salt, hydrate or solvate of the parentcompound.

As used herein, the term “alkyl” refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-6, 1-4,or 1-3 carbon atoms, referred to herein as C.sub.1-C.sub.6alkyl,C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.3 alkyl, respectively.Exemplary alkyl groups include, but are not limited to, methyl, ethyl,propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, etc.

As used herein, the terms “halo” or “halogen” as used herein refer to F,Cl, Br, or I.

As used herein, the term “alkenyl” refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched and having the indicated number of carbon atoms.Preferably alkenyl contains one carbon to carbon double bond, and up tofour nonaromatic carbon-carbon double bonds may be present. Examples ofalkenyl groups include ethenyl, propenyl, n-butenyl, 2-methyl-1-butenyl,3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

As used herein, the term “pharmaceutically acceptable” means approved orapprovable by a regulatory agency of the Federal government of theUnited States of America or the corresponding agency in countries otherthan the United States of America (such as the EMA, the EuropeanMedicines Agency), or that is listed in the United States Pharmacopeiaor European Pharmacopoeia (Ph. Eur.).

As used herein, the term “bioavailable” is art-recognized and refers toa form of the subject disclosure that allows for it, or a portion of theamount administered, to be absorbed by, incorporated to, or otherwisephysiologically available to a subject or patient to whom it isadministered.

As used herein, the terms “treating” or “treatment” of a diseaseincludes inhibiting the disease (slowing or arresting or partiallyarresting its development), preventing the disease, providing relieffrom the symptoms or side effects of the disease (including palliativetreatment), and/or relieving the disease (causing regression of thedisease.

As used herein, a “patient,” “subject” or “host” to be treated by thesubject method may mean either a human or non-human animal. Non-humananimals include companion animals (e.g. cats, dogs) and animals raisedfor consumption (i.e. food animals), such as cows, pigs, chickens.

As used herein, the term “neuroprotection” refers to the prevention orinhibition of degenerative effects of injury or disease in the NS,including protection from the secondary neurodegenerative effects whichpersist even when the primary risk factor is removed or attenuated.

The present disclosure provides a novel honokiol derivative withenhanced stability and surprisingly good bioavailability. Particularly,the compound of the present invention can be used to prepare parenteralor injectable drug delivery.

In one aspect, the present disclosure provides a compound having thefollowing formula:

whereinX is (CH₂)₁₋₆;R₁ is phosphate or carbonate;R₂ and R₃ are each independently C₂₋₆alkenyl, C₁₋₁₀alkyl, —O—C₁₋₁₀alkylor —NH—C₁₋₁₀alkyl, wherein the alkyl or alkenyl is unsubstituted orsubstituted;R₄ and R₅ are each independently one to three H, halogen, —OH, —NH₂,NO₂, C₁₋₁₀alkyl, C₂₋₆alkenyl, —O—C₁₋₁₀alkyl or —NH—C₁₋₁₀alkyl;or a pharmaceutically acceptable salt thereof.

In one embodiment, R₁ is phosphate; R₂ and R₃ are each independentlyC₂₋₆alkenyl; and R₄ and R₅ are each independently H. In a furtherembodiment, R₂ and R₃ are each independently ethenyl.

The pharmaceutically acceptable salts as used herein refer to saltsprepared from pharmaceutically acceptable non-toxic bases includinginorganic bases and organic bases. Salts derived from inorganic basesinclude aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic salts, manganous, potassium, sodium, zinc, and thelike. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like. In one embodiment, thepharmaceutically acceptable salt is a sodium salt.

In one embodiment, the compound of the present invention is3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl bis(phosphate) or sodium3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl bis(phosphate).

The present disclosure provides a preparation method of a honokiolderivative represented by formula (I). The synthetic procedure forhonokiol phosphate (3) is illustrated in the following scheme 1.Honokiol (Compound 1) as a starting substance was reacted with dibenzylphosphite in the presence of N-chlorosuccinimide to afford compound 2.The benzyl groups of the resulting product were removed usingbromotrimethylsilane followed by basification by sodium methoxide toobtain the corresponding phosphate 3.

Reagents and conditions: (a) N-chlorosuccinimide, dibenzyl phosphite,DMAP, DIEA, acetonitrile; (b) i. bromotrimethylsilane, CH₂Cl₂; ii.sodium methoxide, EtOH.

In order to use the compound of Formula (I) in therapy, it will normallybe formulated into a pharmaceutical composition in accordance withstandard pharmaceutical practice.

The present disclosure therefore provides a pharmaceutical composition,which comprises a therapeutically effective amount of a compound ofFormula (I) and optionally one or more pharmaceutically acceptablecarriers and/or excipients.

The present disclosure also provides a dosage form comprising thepharmaceutical composition of the invention. In one embodiment, thedosage form is an injection dosage form.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral administration and, as such, may be in the formof tablets, capsules, oral liquid preparations, powders, granules, orlozenges.

Compositions containing the active ingredient may be in any formsuitable for the intended method of administration. In some embodiments,the compounds of a method and/or composition described herein can beprovided via oral administration, rectal administration, transmucosaladministration, intestinal administration, enteral administration,topical administration, transdermal administration, intrathecaladministration, intraventricular administration, intraperitonealadministration, intranasal administration, intraocular administrationand/or parenteral administration.

The terms “parenteral administration” and “administered parenterally”are art-recognized and refer to modes of administration other thanenteral and topical administration, usually by injection, and includes,without limitation, intravenous, intramuscular, intracranial,intraarterial, intrathecal, intracapsular, intraorbital, intracardiac,intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular,intra-articular, subcapsular, subarachnoid, intraspinal, andintrasternal injection and infusion. For example, Formulations suitablefor parenteral administration include aqueous and non-aqueous isotonicsterile injection solutions which may contain, for example,antioxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose sealed containers, for example, ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

When the compounds are administered via oral administration, forexample, tablets, troches, lozenges, aqueous or oil suspensions,dispersible powders or granules, emulsions, hard or soft capsules,syrups or elixirs may be prepared. Compositions intended for oral usemay be prepared according to any method known to the art for themanufacture of pharmaceutical compositions and such compositions maycontain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable. These excipients maybe, for example, inert diluents, such as calcium or sodium carbonate,lactose, calcium or sodium phosphate; granulating and disintegratingagents, such as maize starch, or alginic acid; binding agents, such asstarch, gelatin or acacia; and lubricating agents, such as magnesiumstearate, stearic acid or talc. Tablets may be uncoated or may be coatedby known techniques including microencapsulation to delay disintegrationand adsorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate alone orwith a wax may be employed.

In some embodiments unit dosage formulations contain a daily dose orunit, daily sub-dose, or an appropriate fraction thereof, of a drug. Inone embodiment, the unit dosage formulation is an injection dosage form.It will be understood, however, that the specific dose level for anyparticular patient will depend on a variety of factors including theactivity of the specific compound employed; the age, body weight,general health, sex and diet of the individual being treated; the timeand route of administration; the rate of excretion; other drugs whichhave previously been administered; and the severity of the particulardisease undergoing therapy, as is well understood by those skilled inthe art.

In a further aspect there is provided a method of antagonizingglycoprotein VI receptor, comprising administration of a therapeuticallyeffective amount of the compound of Formula (I) to the subject. In oneembodiment, the compound can inhibit platelet aggregation.

Glycoprotein (GP) VI is a platelet membrane protein with a molecularweight of 62 kDa that was identified as a physiological collagenreceptor from studies of patients deficient in this protein.GPVI-deficient platelets lacked specifically collagen-inducedaggregation and the ability to form thrombi on a collagen surface underflow conditions, suggesting that GPVI makes an indispensablecontribution to collagen-induced platelet activation.

The present invention also provides a method of providing antioxidantand neuroprotective effects in a subject, comprising administering atherapeutically effective amount of the compound of Formula (I) to thesubject.

The present disclosure also provides a method of improving brain damagein a subject, which comprises administration of a therapeuticallyeffective amount of the compound of Formula (I) to the subject. In oneembodiment, the brain damage is ischemic stroke.

In one embodiment, the methods described herein do not cause hemorrhage.

In one embodiment, the methods described herein reduces edema.

In the methods described herein, the compound of the present disclosurehas a prolonged half-life compared to honokiol.

In the methods described herein, the compound of the present disclosureconverts to honokiol in plasma.

The dose range of the compounds of general formula (I) applicable perday is usually from about 0.01 to about 1.0 mg per kg body weight,preferably from about 0.025 to about 1.0, about 0.05 to about 1.0, about0.075 to about 1.0, about 0.025 to about 0.1, about 0.05 to about 0.1,about 0.75 to about 0.1, about 0.1 to about 1.0, about 0.25 to about1.0, about 0.5 to about 1.0 or about 0.75 to about 1.0 mg per kg bodyweight of the patient.

The examples which follow are intended in no way to limit the scope ofthe disclosure but are provided to illustrate how to prepare and usecompounds disclosed herein. Many other embodiments of this disclosurewill be apparent to one skilled in the art.

EXAMPLE Example 1 Preparation of Tetrabenzyl(3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl) bis(phosphate) (2) (HP-TMU)

A solution of N-chlorosuccinimide (5.0 equiv) in CH₃CN was heated at 40°C. for 5 min. A solution of dibenzyl phosphite (5.0 equiv) in CH₃CN wasadded to this prepared solution and stirred at room temperature for 4hours. Meanwhile, a solution of honokiol (1, 1 equiv),N,N-diisopropylethylamine (DIPEA, 5.0 equiv), and4-dimethylaminopyridine (DMAP, 0.2 equiv) in CH₃CN was prepared andadded to the stirring mixture at room temperature. The resulting mixturewas stirred at room temperature for 1 hour. The reaction mixture wasquenched by H₂O and extracted with toluene. The organic layer wascollected and dried to afford tetrabenzyl(3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl) bis(phosphate) (referred ascompound 2).

Example 2 Preparation of Sodium 3′,5-diallyl-[1,1′-biphenyl]-2,4′-diylbis(phosphate) (3)

Bromotrimethylsilane was added to a solution of compound 2 (1 equiv) inCH₂Cl₂ was added bromotrimethylsilane under ice bath and stirred at roomtemperature for 3 hours. The reaction mixture was quenched by H₂O andextracted with ethyl acetate. The aqueous layer was collected and driedto afford a crude product. The resulting residue was dissolved in EtOHand then sodium methoxide (4.4 equiv) was added. After stirring at roomtemperature for 18 hours, the organic solvent was removed in vacuum. Theresulting residue was dissolved in H₂O and extracted with ethyl acetate.The aqueous layer was collected and dried to afford sodium3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl bis(phosphate) (referred to ascompound 3).

Example 3 HP-TMU Exerts (1) Superior Neuroprotective Effects AgainstEmbolic Stroke as Compared to Honokiol (2) without Causing the Risk ofHemorrhagic Incidence in Mice

Coronal sections of 2,3,5-triphenyltetrazolium chloride (TTC)-stainedbrains were taken after middle cerebral artery occlusion (MCAO) in thevehicle group treated with an isovolumetric solvent (normal saline,intravenous [i.v.]), and groups treated with HP-TMU (0.25, 0.5 and 1mg/kg, i.v.) or honokiol (0.129, 0.258 and 0.516 mg/kg, i.v.; the dosesof honokiol were adjusted by the ratio of the molecular weight ofhonokiol to HP-TMU (266.33/514.22)) after 30 min-embolic occlusion. Thedensitometric analyses for the measurement of infarct volume and brainedema were performed after treatment with HP-TMU or honokiol againstembolic stroke in mice. Bleeding time was measured 10 min after the i.v.administration of normal saline (isovolumetric control) or HP-TMU (0.5and 1 mg/kg, i.v.) for 30 min.

As shown in FIG. 1A, the red region in the TTC-stained sectionsindicates the nonischemic portion of the brain, whereas the pale regionindicates the ischemic portion. Treatment with HP-TMU (0.5 and 1 mg/kg)significantly reduced the infarct volume compared with that in thesolvent control group (P<0.05) (FIG. 1B). In addition, MCAO-inducedcerebral edema in the ischemic hemisphere was reduced by the treatmentof 1 mg/kg HP-TMU (FIG. 1C). Furthermore, the administration of HP-TMUreveals more potent neuroprotective effects than honokiol in micesubjected to MCAO (FIGS. 1A-1C). On the other hand, increased risk ofhemorrhage is a major side effect of anti-stroke treatments. To evaluateHP-TMU in this aspect, we used the mouse tail transection model as anindex of hemostasis. As shown in FIG. 2, HP-TMU (0.5 and 1 mg/kg) didnot alter the bleeding time substantially, illustrating that HP-TMUtreatment for embolic stroke is harmless, eliciting no side effects ofbleeding.

Example 4 HP-TMU Improves Neurobehavioral Functions in Mice after MCAO

Mice were subjected to middle cerebral artery occlusion (MCAO) surgeryfor 30 min, and then treated with the isovolumetric vehicle control(normal saline, intravenous [i.v.]) or HP-TMU (0.25, 0.5 and 1 mg/kg,i.v.) or honokiol (0.129, 0.258 and 0.516 mg/kg, i.v.). Assays ofneurobehavioral functions includeneurological severity scoring and therotarod test. Evaluations were performed before and 24 and 48 h aftersurgery.

Neurological deficit was examined and scored on an 18-point scale beforeand 24 and 48 h after MCAO reperfusion injury. The changes inneurological deficit scores of different groups are illustrated in FIG.3A. At 24 and 48 h after MCAO, neurobehavioral deficit scoressignificantly increased compared with those before MCAO; nevertheless,0.5 and 1 mg/kg HP-TMU significantly ameliorated these increased scores(Post-24 h groups: P<0.05; Post-48 h groups: P<0.05). In addition, theperformance of the MCAO group mice in the rotarod test at 24 and 48 hafter MCAO was also impaired, and the decrease of rotarod duration wassignificant reversed in the HP-TMU (0.5 and 1 mg/kg)-treated micecompared with the vehicle control group (Post-24 h groups: P<0.05;Post-48 h groups: P<0.05) (FIG. 3B). Mean plasma concentrations ofhonokiol vs. time profile in five rats were measured after intravenousinjection of HP-TMU or honokiol.

The plasma concentrations of honokiol at different points are expressedas mean±SD, and the mean concentration-time curve is shown in FIG. 4A.The calculated pharmacokinetic parameters of HP-TMU are summarized inFIG. 4B. The results revealed that intravenous administration ofhonokiol (0.258 mg/kg) rapidly distributed and could not be detected inplasma. However, the same dosage of HP-TMU (0.5 mg/kg) could behydrolyzed to honokiol and be detected in rat plasma. HP-TMU hasprolonged half-life compared to honokiol, and it was indeed converted tohonokiol in plasma.

Example 5 Comparison of the Neuroprotective Effect of HP-TMU andEdaravone in Mice Subjected to MCAO

Mice were subjected to middle cerebral artery occlusion (MCAO) surgeryfor 30 min, and then treated with the isovolumetric vehicle control(normal saline, intravenous [i.v.]) or HP-TMU (1 mg/kg, i.v.) oredaravone (3 mg/kg, i.v.). The therapeutic effects of HP-TMU onlong-term recovery were evaluated by neurological severity scoringbefore or 1, 2, 7, 14, and 28 days after surgery.

The long-term recovery of neurological deficit of MCAO mice weresignificantly improved by the treatment of HP-TMU (1 mg/kg) at 1, 2, and7 days after surgery (FIG. 5). In addition, the administration of HP-TMU(1 mg/kg) reveals similar therapeutic effects compared with edaravone (3mg/kg), an approved drug in Japan to treat acute ischemic stroke (FIG.5).

What is claimed is:
 1. A compound having the following Formula (I),

wherein X is (CH₂)₁₋₆; R₁ is phosphate or carbonate; R₂ and R₃ are eachindependently C₂₋₆alkenyl, C₁₋₁₀alkyl, —O—C₁₋₁₀alkyl or —NH—C₁₋₁₀alkyl,wherein the alkyl or alkenyl is unsubstituted or substituted; and R₄ andR₅ are each independently one to three H, halogen, —OH, —NH₂, NO₂,C₁₋₁₀alkyl, C₂₋₆ alkenyl, —O—C₁₋₁₀alkyl or —NH—C₁₋₁₀alkyl; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein R₁ is phosphate; R₂ and R₃ are each independently C₂₋₆alkenyl;and R₄ and R₅ are each independently H; or a pharmaceutically acceptablesalt thereof.
 3. The compound of claim 1, wherein R₂ and R₃ are eachindependently ethenyl; or a pharmaceutically acceptable salt thereof. 4.The compound of claim 1, wherein the pharmaceutically acceptable salt isa sodium salt.
 5. The compound of claim 1, which is3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl bis(phosphate), or apharmaceutically acceptable salt thereof.
 6. The compound of claim 1,which is sodium 3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl bis(phosphate).7. A pharmaceutical composition, which comprises a therapeuticallyeffective amount of a compound of claim 1 and optionally one or morepharmaceutically acceptable carriers and/or excipients.
 8. Thepharmaceutical composition of claim 7, which is in a dosage form.
 9. Thepharmaceutical composition of claim 8, wherein the dosage form is aninjection dosage form.
 10. A method of antagonizing glycoprotein VIreceptor, comprising administration of a therapeutically effectiveamount of a compound of claim 1 to a subject.
 11. The method of claim10, wherein the platelet aggregation can be inhibited.
 12. A method ofproviding antioxidant and neuroprotective effects in a subject,comprising administering a therapeutically effective amount of acompound of claim 1 to a subject.
 14. The method of claim 12, whereinthe method does not cause hemorrhage.
 15. The method of claim 12,wherein the method reduces edema.
 16. The method of claim 12, whereinthe compound has a prolonged half-life compared to honokiol.
 17. Themethod of claim 12, wherein the compound converts to honokiol in plasma.18. The method of claim 12, wherein the neuroprotective effectdiminishes brain damage in the subject.
 19. The method of claim 18,wherein the brain damage is ischemic stroke.
 20. The method of claim 12,wherein the administration is parenteral administration.
 21. The methodof claim 20, wherein the parenteral administration is intravenous,intramuscular or intracranial administration.